It has been known that conventional non-steroidal anti-inflammatory drugs (NSAIDs), representatives of which include aspirin, indomethacin, etc., control the biosynthesis of prostaglandins, certain chemical mediators for inflammation, via the inhibition of cyclooxygenase (COX) which is a synthase responsible for the formation of prostaglandins from arachidonic acid, thereby exerting anti-inflammatory action. However, prostaglandins are involved in a variety of physiological actions including not only inflammation but also the inhibition of gastric secretion and the increase of mucosal blood flow. Since the conventional NSAIDs also inhibit the biosynthesis of certain prostaglandins responsible for other physiological roles than inflammation, they frequently have a high potential for raising adverse side effects such as attacks on gastric mucosa and kidney. Accordingly, the clinical usefulness of the NSAIDs is often restricted.
Recently, it has been found that there are isozymes of COX. Thus, one form of COX, named "COX-1", which has been known in the art up until recently, exists systemically and constantly in stomach, kidney, etc. Another form of COX, named "COX-2", which has been discovered newly, is inducible at the site of an inflammatory stimulus. It is believed that the conventional NSAIDs inhibit both COX-1 and COX-2, with the result that such side effects appear. When selective COX-2 inhibitors are available, it is therefore expected that such selective COX-2 inhibitors would exert predominantly desirable anti-inflammatory action whereby they would reduce the aforementioned side effects entailed by the conventional NSAIDs with non-selective COX inhibiting activity.
From such an angle, up until now, some compounds have been synthesized with a view to exploring selective COX inhibitors. For anti-inflammatory pyrazole derivatives among them, those disclosed in JP, 1-52758, A (1989); JP, 3-141261, A (1991); JP, 5-246997, A (1993); etc., have been known. Further, WO, 95/15315, Al (1995); WO, 95/15316, Al (1995); WO, 95/15318, Al (1995); etc., disclose pyrazole derivatives, part of which have selective COX-2 inhibitory and anti-inflammatory activity.
However, these compounds are not satisfactory medicaments for solving the above problems, so the development of anti-inflammatory drugs with significantly selective COX-2 inhibiting activity together with more advantageous pharmacological action and safety is still desired.